MSAll策略，通过LC高分辨率qq-TOF质谱结合所有碎片离子谱图的全窗口采集，对PEG化阿霉素，PEG和阿霉素进行全面定量分析,Analyst

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MSAll策略，通过LC高分辨率qq-TOF质谱结合所有碎片离子谱图的全窗口采集，对PEG化阿霉素，PEG和阿霉素进行全面定量分析
Analyst ( IF 3.6 ) Pub Date : 2017-10-06 00:00:00 , DOI: 10.1039/c7an00470b
Lei Yin _{1,

2,

3,

4,

5} , Chong Su _{4,

5,

6,

7,

8} , Tianming Ren _{4,

5,

6,

7,

8} , Xiangjun Meng _{4,

5,

6,

7,

8} , Meiyun Shi _{4,

9,

10,

11} , J. Paul Fawcett _{12,

13,

14,

15} , Mengliang Zhang _{16,

17,

18,

19} , Wei Hu _{1,

2,

3,

4} , Jingkai Gu _{1,

2,

3,

4,

5}

Affiliation

Research Institute of Translational Medicine
The First Hospital of Jilin University
Changchun 130061
PR China
Research Center for Drug Metabolism
School of Life Science
Jilin University
Changchun 130012
School of Life and Medical Sciences
Dalian University of Technology
New District of Liaodong Bay, Panjin124221
School of Pharmacy
University of Otago
Dunedin
New Zealand
Department of Chemistry
Middle Tennessee State University
Murfreesboro
USA

聚乙二醇（PEG）与治疗化合物的共价结合（称为PEG化）是提高小分子量药物生物学功效的最有前途的技术之一。给药后，聚乙二醇化的前药可以代谢为药理活性化合物，从而聚乙二醇化的药物，游离药物和释放的PEG同时存在于体内。需要了解这三种化合物的药代动力学行为，以指导聚乙二醇化治疗药物的开发。但是，PEG是分子量范围很宽的多分散分子，因此在生物基质中同时定量PEG和PEG化的分子非常具有挑战性。本文报道正离子模式下基于液相色谱电喷雾电离四极杆飞行时间质谱（LC-qq-TOF-MS）的数据独立采集方法（MSAll）在同时测定甲氧基PEG2000-大鼠血液中的阿霉素（mPEG2K-Dox）及其分解产物。使用MSAll技术，在q1中生成所有分子的前体离子，在q2中（碰撞池）破碎成产物离子，并进行TOF分离，然后分别以不同的低和高碰撞能（CE）记录前体离子和产物离子。单次进样的实验。在这项研究中，q2的解离生成了一系列与m / z 89.0611、133.0869、177.1102、221.1366、265.1622、309.1878和353相关的高分辨率PEG相关产物离子。2108对应于包含各种数目的环氧乙烷亚基，m / z为321.0838和361.0785的Dox相关产物离子以及m / z 365.0735为mPEG2K-Dox特定产物离子的片段。mPEG和mPEG2K-Dox的检测基于mPEG和特定化合物的高分辨率提取离子。该方法已成功应用于大鼠单次静脉内注射mPEG2K-阿霉素后，对阿霉素，mPEG2K（甲基化聚乙二醇2K）和mPEG2K-阿霉素进行了药代动力学研究。据我们所知，这是同时测定生物基质中的mPEG，Dox和mPEG2K-Dox的第一种方法。我们相信，本研究中使用的MSAll技术可以潜在地扩展到其他PEG化的小分子或高分子化合物的测定。

"点击查看英文标题和摘要"

MSAll strategy for comprehensive quantitative analysis of PEGylated-doxorubicin, PEG and doxorubicin by LC-high resolution q-q-TOF mass spectrometry coupled with all window acquisition of all fragment ion spectra

The covalent attachment of polyethylene glycol (PEG) to therapeutic compounds (known as PEGylation) is one of the most promising techniques to improve the biological efficacy of small molecular weight drugs. After administration, PEGylated prodrugs can be metabolized into pharmacologically active compounds so that PEGylated drug, free drug and released PEG are present simultaneously in the body. Understanding the pharmacokinetic behavior of these three compounds is needed to guide the development of pegylated theranostic agents. However， PEGs are polydisperse molecules with a wide range of molecular weights, so that the simultaneous quantitation of PEGs and PEGylated molecules in biological matrices is very challenging. This article reports the application of a data-independent acquisition method (MSAll) based on liquid chromatography electrospray ionization quadrupole time-of-flight mass spectrometry (LC-q-q-TOF-MS) in the positive ion mode to the simultaneous determination of methoxyPEG2000-doxorubicin (mPEG2K-Dox) and its breakdown products in rat blood. Using the MSAll technique, precursor ions of all molecules are generated in q1, fragmented to product ions in q2 (collision cell), and subjected to TOF separation before precursor and product ions are recorded using low and high collision energies (CE) respectively in different experiments for a single sample injection. In this study, dissociation in q2 generated a series of high resolution PEG-related product ions at m/z 89.0611, 133.0869, 177.1102, 221.1366, 265.1622, 309.1878, and 353.2108 corresponding to fragments containing various numbers of ethylene oxide subunits, Dox-related product ions at m/z 321.0838 and 361.0785, and an mPEG2K-Dox specific product ion at m/z 365.0735. Detection of mPEGs and mPEG2K-Dox was based on high resolution extracted ions of mPEG and the specific compound. The method was successfully applied to a pharmacokinetic study of doxorubicin, mPEG2K (methylated polyethylene glycol 2K), and mPEG2K-doxorubicin in rats after a single intravenous injection of mPEG2K-doxorubicin. To the best of our knowledge, this is the first assay that simultaneously determines mPEG, Dox, and mPEG2K-Dox in a biological matrix. We believe the MSAll technique as applied in this study can be potentially extended to the determination of other PEGylated small molecules or polymeric compounds.

更新日期：2017-10-07

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